Maintenance of energy balance in an ever-changing environment requires the brain to cope with a variety of genetic and physiologic insults. Compensatory regulation of energy balance is frequently observed but its underlying mechanisms remain largely unknown. We have recently shown that hypothalamic neurons important for energy balance regulation can be regenerated in adult hypothalamus in response to progressive degeneration of orexigenic AgRP/NPY neurons, and that inhibition of cell proliferation in the mutant brain affects feeding and adiposity. Our results suggest that regulation of cell proliferation in the adult hypothalamus could serve as a compensatory mechanism to maintain hypothalamic feeding functions. To date, the functional role of adult neurogenesis in energy balance regulation remains largely unexplored. Hypothalamus is generally considered non-neurogenic in the adulthood although abundant neural progenitor cells are present. However, neurodegeneration has been shown to be a potent stimulus of neurogenesis in normally non-neurgenic regions of the brain in both rodents and humans. In this proposal, we will test the hypothesis that modulation of cell proliferation in the adult hypothalamus serves as a repair mechanism to limit the extent of energy imbalance under pathophysiologic conditions. Specifically, we will examine the spatiotemporal activation of neural progenitor cells in the adult hypothalamus in response to degeneration of specific hypothalamic neurons. We will determine whether adult born hypothalamic neurons can respond appropriately to alteration of energy balance status and peripheral metabolic hormones. We will examine survival and projection outgrowth of these adult born neurons and their synaptic connectivity. In addition, we will evaluate hypothalamic neurogenic activity during chronic obesity and diabetes, conditions that are associated with decreased brain volume and neuronal cell death in rodents and humans. By using a temporally inducible and cell type specific cell ablation approach, we will determine the functional significance of adult neural progenitors in compensatory regulation of energy balance under normal, obese and diabetes conditions. Finally, We will investigate neurogenic activity of transplanted neural progenitor cells in adult hypothalamus, and explore therapeutic potential of neural progenitor cell transplantation in treatment of obesity caused by neurodegeneration of hypothalamic neurons. Together, our study will provide critical information on the role of neurogenesis in compensatory regulation of energy balance. It will provide novel insight into therapeutic potential of neural stem cells in treatment of hypothalamic neurodegeneration that are associated with a variety of chronic diseases and brain injuries. PUBLIC HEALTH RELEVANCE: In this proposal, we will test the hypothesis that modulation of cell proliferation in the adult hypothalamus serves as a repair mechanism to limit the extent of energy imbalance under pathophysiologic conditions such as chronic obesity and diabetes. Our study will determine functional connections between neurodegeneration, neurogenesis and body weight regulation. It will provide novel insight into therapeutic potential of neural stem cells in treatment of hypothalamic neurodegeneration that are associated with a variety of chronic diseases and brain injuries.